Molecularly targeted radiotherapy using 131I-MIBG has been demonstrated to improve survival in neuroblastoma, but the dose is limited by bone marrow toxicity. Similarly, molecularly targeted therapy with 90Y-DOTA-tyr3-Octreotide has improved quality of life in patients with neuroendocrine tumors, but the dose is limited by toxicity to kidneys. We have demonstrated the theoretical advantage of combined radiotherapy targeting the amine transporter (VMAT1) using 131I-MIBG and a somatostatin receptor (sst2) using 90Y-DOTA-tyr3-Octreotide in order to maximize the radiation dose to tumor while minimizing the dose to bone marrow and kidney. We hypothesize that image-guided dosimetry will enable safe and effective delivery of dual-target, dual-isotope radiotherapy that increases therapeutic dose to tumor without dose limiting toxicity to normal tissues. Our long-term goal is to develop individualized, dosimetry- based, combination radiotherapy for pediatric tumors as a major step forward from the current approach of delivering an empiric radiation dose using a single agent. We will focus our efforts on neural crest and neuroendocrine tumors of childhood, such as neuroblastoma and foregut carcinoid, that express both the amine transporter protein, VMAT1, and the type 2 somatostatin receptor (sst2). Individualized normal organ and tumor dosimetry will be performed in children with neuroblastoma or a neuroendocrine tumor using 124I-MIBG PET and 111In- DOTA-tyr3-Octreotide SPECT in order to determine the feasibility of a future Phase I trial of dosimetry based dual-target, dual-isotope radiotherapy with 131I-MIBG and 90Y-DOTA-tyr3-Octreotide. Accordingly, our Specific Aims are: Aim I. Conduct dosimetry studies in children and young adults with neuroblastoma or neuroendocrine tumors. We will determine the patient specific administered amount of radioactivity of 131I-MIBG and 90Y-DOTA-tyr3-Octreotide that would achieve maximum tumor radiation dose without exceeding established dose limits for critical normal organs. Aim II. Determine if immunohistochemistry and/or qPCR analysis of VMAT1 and sst2 on tumor biopsies will predict which children are best candidates for dual-target, dual-isotope radiotherapy. We will characterize VMAT1 and sst2 expression in the initial tumor biopsy prior to any therapy. Based upon the results from testing of our hypothesis through the completion of the above aims, we will determine whether to proceed to a phase I clinical trial using a therapeutic combination of 131I-MIBG plus 90Y-DOTA-tyr3-Octreotide to treat children and young adults with neuroblastoma and neuroendocrine tumors. We will proceed to clinical testing of this therapeutic regimen if our hypothesis is determined to be true for this drug combination. PUBLIC HEALTH RELEVANCE: Molecularly targeted radiotherapy using 131I-MIBG has been demonstrated to improve survival in neuroblastoma, but the dose is limited by bone marrow toxicity. Similarly, molecularly targeted radiotherapy with 90Y-DOTA-tyr3-Octreotide has improved quality of life in patients with neuroendocrine tumors, but the dose is limited by toxicity to kidneys. We have demonstrated the theoretical advantage of combined radiotherapy targeting these two types of tumors using a combination of 131I-MIBG and 90Y-DOTA-tyr3-Octreotide in order to maximize the radiation dose to tumor while minimizing the dose to bone marrow and kidney. Our long-term goal is to develop patient specific, combination radiotherapy for pediatric tumors as a major step forward from the current approach of delivering an "average patient" radiation dose using a single agent.